Dataset Information

MyD88 and TLR4 Expression in Epithelial Ovarian Cancer.

ABSTRACT: OBJECTIVE:To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. PATIENTS AND METHODS:We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). RESULTS:Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively). CONCLUSION:Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.

SUBMITTER: Block MS

PROVIDER: S-EPMC5870793 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MyD88 and TLR4 Expression in Epithelial Ovarian Cancer.

Block Matthew S MS Vierkant Robert A RA Rambau Peter F PF Winham Stacey J SJ Wagner Philipp P Traficante Nadia N Tołoczko Aleksandra A Tiezzi Daniel G DG Taran Florin Andrei FA Sinn Peter P Sieh Weiva W Sharma Raghwa R Rothstein Joseph H JH Ramón Y Cajal Teresa T Paz-Ares Luis L Oszurek Oleg O Orsulic Sandra S Ness Roberta B RB Nelson Gregg G Modugno Francesmary F Menkiszak Janusz J McGuire Valerie V McCauley Bryan M BM Mack Marie M Lubiński Jan J Longacre Teri A TA Li Zheng Z Lester Jenny J Kennedy Catherine J CJ Kalli Kimberly R KR Jung Audrey Y AY Johnatty Sharon E SE Jimenez-Linan Mercedes M Jensen Allan A Intermaggio Maria P MP Hung Jillian J Herpel Esther E Hernandez Brenda Y BY Hartkopf Andreas D AD Harnett Paul R PR Ghatage Prafull P García-Bueno José M JM Gao Bo B Fereday Sian S Eilber Ursula U Edwards Robert P RP de Sousa Christiani B CB de Andrade Jurandyr M JM Chudecka-Głaz Anita A Chenevix-Trench Georgia G Cazorla Alicia A Brucker Sara Y SY Alsop Jennifer J Whittemore Alice S AS Steed Helen H Staebler Annette A Moysich Kirsten B KB Menon Usha U Koziak Jennifer M JM Kommoss Stefan S Kjaer Susanne K SK Kelemen Linda E LE Karlan Beth Y BY Huntsman David G DG Høgdall Estrid E Gronwald Jacek J Goodman Marc T MT Gilks Blake B García María José MJ Fasching Peter A PA de Fazio Anna A Deen Suha S Chang-Claude Jenny J Candido Dos Reis Francisco J FJ Campbell Ian G IG Brenton James D JD Bowtell David D DD Benítez Javier J Pharoah Paul D P PDP Köbel Martin M Ramus Susan J SJ Goode Ellen L EL

Mayo Clinic proceedings 20180301 3

<h4>Objective</h4>To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival.<h4>Patients and methods</h4>We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and ...[more]

PMID: 29502561

Similar Datasets

Project description:Despite the use of front-line anticancer drugs such as paclitaxel for ovarian cancer treatment, mortality rates have remained almost unchanged for the past three decades and the majority of patients will develop recurrent chemoresistant disease which remains largely untreatable. Overcoming chemoresistance or preventing its onset in the first instance remains one of the major challenges for ovarian cancer research. In this study, we demonstrate a key link between senescence and inflammation and how this complex network involving the biomarkers MAD2, TLR4 and MyD88 drives paclitaxel resistance in ovarian cancer. This was investigated using siRNA knockdown of MAD2, TLR4 and MyD88 in two ovarian cancer cell lines, A2780 and SKOV-3 cells and overexpression of MyD88 in A2780 cells. Interestingly, siRNA knockdown of MAD2 led to a significant increase in TLR4 gene expression, this was coupled with the development of a highly paclitaxel-resistant cell phenotype. Additionally, siRNA knockdown of MAD2 or TLR4 in the serous ovarian cell model OVCAR-3 resulted in a significant increase in TLR4 or MAD2 expression respectively. Microarray analysis of SKOV-3 cells following knockdown of TLR4 or MAD2 highlighted a number of significantly altered biological processes including EMT, complement, coagulation, proliferation and survival, ECM remodelling, olfactory receptor signalling, ErbB signalling, DNA packaging, Insulin-like growth factor signalling, ion transport and alteration of components of the cytoskeleton. Cross comparison of the microarray data sets identified 7 overlapping genes including MMP13, ACTBL2, AMTN, PLXDC2, LYZL1, CCBE1 and CKS2. These results demonstrate an important link between these biomarkers, which to our knowledge has never before been shown in ovarian cancer. In the future, we hope that triaging patients into alterative treatment groups based on the expression of these three biomarkers or therapeutic targeting of the mechanisms they are involved in will lead to improvements in patient outcome and prevent the development of chemoresistance.

Project description:BACKGROUND:Previous studies indicate that soyasaponins may reduce inflammation via modulating toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling. However, its underlying mechanisms are still not fully understood. METHODS:Lipopolysaccharide (LPS)-challenged inflamed male ICR mice were intervened by intragastrical administration with 10 and 20??mol/kg·BW of soyasaponin A1, A2 or I for 8?weeks. The serum inflammatory markers were determined by commercial kits and the expression of molecules in TLR4/MyD88 signaling pathway in liver by real-time PCR and western blotting. The recruitments of TLR4 and MyD88 into lipid rafts of live tissue lysates were detected by sucrose gradient ultracentrifugation and western blotting. LPS-stimulated RAW264.7 macrophages were treated with 10, 20 and 40??mol/L of soyasaponin A1, A2 or I for 2?h. MyD88-overexpressed HEK293T cells were treated with 20 and 40??mol/L of soyasaponins (A1, A2 or I) or 20??mol/L of ST2825 (a MyD88 inhibitor) for 6?h. The expression of molecules in TLR4/MyD88 signaling pathway were determined by western blotting. Data were analyzed by using one way analysis of variance or t-test by SPSS 20.0 statistical software. RESULTS:Soyasaponins A1, A2 or I significantly reduced the levels of tumor necrosis factor alpha (TNF?), interleukin (IL)-6 and nitric oxide (NO) in serum (p?<?0.05), and decreased the mRNA levels of TNF?, IL-6, IL-1?, cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) (p?<?0.05), the protein levels of myeloid differentiation protein 2 (MD-2), TLR4, MyD88, toll-interleukin1 receptor domain containing adaptor protein (TIRAP), phosphorylated interleukin-1 receptor-associated kinase 4 (p-IRAK-4), phosphorylated interleukin-1 receptor-associated kinase 1 (p-IRAK-1) and TNF receptor associated factor 6 (TRAF6) (p?<?0.05), and the recruitments of TLR4 and MyD88 into lipid rafts in liver (p?<?0.05). In LPS-stimulated macrophages, soyasaponins A2 or I significantly decreased MyD88 (p?<?0.05), soyasaponins A1, A2 or I reduced p-IRAK-4 and p-IRAK-1 (p?<?0.05), and soyasaponin I decreased TRAF6 (p?<?0.05). In MyD88-overexpressed HEK293T cells, soyasaponins (A1, A2 or I) and ST2825 significantly decreased MyD88 and TRAF6 (p?<?0.05). CONCLUSION:Soyasaponins can reduce inflammation by downregulating MyD88 expression and suppressing the recruitments of TLR4 and MyD88 into lipid rafts. This study provides novel understanding about the anti-inflammatory mechanism of soyasaponins.

Project description:BACKGROUND:ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. METHODS:The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided. RESULTS:Associations with outcome were observed with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration. CONCLUSIONS:Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.

Dataset Information

MyD88 and TLR4 Expression in Epithelial Ovarian Cancer.

Publications

MyD88 and TLR4 Expression in Epithelial Ovarian Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets